title: Peroxisome proliferator-activated receptor-α is renoprotective in doxorubicin-induced glomerular injury.
abstract: Doxorubicin (DOX) is an anthracycline antibiotic utilized in antitumor therapy; however, its clinical use is frequently impeded by renal toxic effects. As peroxisome proliferator-activated receptor-α (PPAR-α) has renoprotective effects in drug-related kidney injuries, we tested its ability to inhibit DOX-induced renal injury. Although both male PPAR-α knockout mice and their wild-type littermates (pure 129/SvJ background) had significant proteinuria 4 weeks after DOX treatment, those with deletion of PPAR-α had more severe proteinuria. This was associated with more serious podocyte foot process effacement compared with wild-type mice. In contrast, the PPAR-α agonist fenofibrate effectively reduced proteinuria and attenuated DOX-induced podocyte foot process effacement. Consistently, glomerular nephrin expression was significantly lower in the knockout compared with wild-type mice following DOX treatment. Fenofibrate therapy significantly blunted the reduction in glomerular nephrin levels in DOX-treated wild-type mice. In cultured podocytes, DOX induced apoptosis, increased cleaved caspase-3 levels, and decreased Bcl-2 expression, all attenuated by pretreatment with fenofibrate. Thus, PPAR-α deficiency exacerbates DOX-related renal injury, in part, due to increased podocyte apoptosis.
authors.affiliation: Department of Physiology and Pathophysiology, Peking University Health Science Center, Beijing, China.
authors.forename: Yunfeng
authors.initials: Y
authors.lastname: Zhou
authors.forename: Xiaomu
authors.initials: X
authors.lastname: Kong
authors.forename: Pan
authors.initials: P
authors.lastname: Zhao
authors.forename: Hang
authors.initials: H
authors.lastname: Yang
authors.forename: Lihong
authors.initials: L
authors.lastname: Chen
authors.forename: Jing
authors.initials: J
authors.lastname: Miao
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Zhang
authors.forename: Jichun
authors.initials: J
authors.lastname: Yang
authors.forename: Jie
authors.initials: J
authors.lastname: Ding
authors.forename: Youfei
authors.initials: Y
authors.lastname: Guan
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D002460:Cell Line; D019610:Cytoprotection; D004195:Disease Models, Animal; D004317:Doxorubicin; D011345:Fenofibrate / Q000494:pharmacology; D007674:Kidney Diseases / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D007678:Kidney Glomerulus / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D057507:Mice, 129 Strain; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D047493:PPAR alpha / Q000819:agonists / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D050199:Podocytes / Q000378:metabolism / Q000473:pathology; D011507:Proteinuria / Q000378:metabolism / Q000517:prevention & control; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D013045:Species Specificity; D013997:Time Factors; D014158:Transcription, Genetic
chemical_list: D008565:Membrane Proteins; D047493:PPAR alpha; D019253:Proto-Oncogene Proteins c-bcl-2; C113267:nephrin; D004317:Doxorubicin; C505409:Casp3 protein, mouse; D053148:Caspase 3; D011345:Fenofibrate